Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Previously Untreated Pancreatic Cancer That Is Metastatic or Cannot Be Removed by Surgery

• ClinicalTrials.gov Identifier: NCT02194829
• Recruitment Status: Active, not recruiting
• First Posted: July 18, 2014
• Last Update Posted: December 11, 2020
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: July 16, 2014
• First Posted Date: July 18, 2014
• Last Update Posted Date: December 11, 2020
• Actual Study Start Date: July 1, 2014
• Estimated Primary Completion Date: May 21, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 16, 2014)

• Maximum tolerated dose of WEE1 inhibitor MEK-1775, defined as the highest dose level at which < 33% of 6 patients experience a dose-limiting toxicity graded according to Common Terminology Criteria for Adverse Events version 4 (Phase I) [ Time Frame: 4 weeks ]
• Progression-free survival [ Time Frame: From randomization to documented progression or death without progression, assessed up to 2 years ]
  PFS by arm will be compared using one-sided log-rank tests. Cox's proportional hazards models will be used to estimate hazard ratios.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 16, 2014)

• Overall survival [ Time Frame: From randomization to death from any cause, assessed up to 2 years ]
  OS by arm will be compared using one-sided log-rank tests. Cox's proportional hazards models will be used to estimate hazard ratios.
• Response rate (CR + PR) [ Time Frame: Up to 2 years ]
  Will be analyzed using Fisher's exact tests at a one-sided significance level of 0.15.
• Disease control rate (CR + PR + SD) [ Time Frame: Up to 2 years ]
  Will be analyzed using Fisher's exact tests at a one-sided significance level of 0.15.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 16, 2014)

• Change in tumor FDG uptake (SUVmax) [ Time Frame: Baseline to week 4 ]
  Will be evaluated as a predictor of response using RECIST as the reference standard.
• Accuracy of change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET as a predictor of progression-free survival [ Time Frame: Up to week 4 ]
  Time-dependent receiver operator characteristic methodology will be used to assess the ability of SUVmax change to predict PFS.
• Change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET [ Time Frame: Baseline to week 4 ]
  Will be compared between the patients from treatment arms C and D only as a continuous variable using Wilcoxon test and as binary variable (defined as summed SUVmax change from baseline < -25% versus >= -25%) using Fisher's exact tests.
• Incidence of an early increase in tumor FLT uptake (FLT-flare) within 24 hours after initiation of treatment [ Time Frame: Up to 24 hours after initiation of treatment ]
• Incidence of abrogation of early increase in tumor FLT uptake after initiation of treatment [ Time Frame: Up to 24 hours ]
• Change in tumor FLT uptake (SUVmax) [ Time Frame: Baseline to 24 hours after initiation of treatment ]
  Will be compared between patients from treatment arms C and D.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Previously Untreated Pancreatic Cancer That Is Metastatic or Cannot Be Removed by Surgery
• Official Title: A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine With or Without AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas
• Brief Summary: This partially randomized phase I/II trial studies the side effects and best dose of WEE1 inhibitor MK-1775 when given together with paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride and how well they work in treating patients with previously untreated pancreatic cancer that has spread to another place in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. WEE1 inhibitor MK-1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride are more effective with or without WEE1 inhibitor MK-1775 in treating patients with pancreatic cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the toxicity of combination therapy with nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation), gemcitabine (gemcitabine hydrochloride) and AZD1775 (WEE1 inhibitor MK-1775) in patients with treatment-naive metastatic adenocarcinoma of the pancreas or locally-advanced adenocarcinoma of the pancreas which is not surgically resectable. (Phase I) II. To determine the dose of AZD1775 to be used in combination with nab-paclitaxel and gemcitabine chemotherapy in the phase II portion of the trial. (Phase I) III. To determine the pharmacokinetics of AZD1775 in combination with nab-paclitaxel and gemcitabine. (Phase I) IV. To evaluate progression-free survival (PFS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate overall survival (OS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) II. To evaluate response rate (complete response [CR] + partial response [PR]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) III. To evaluate disease control rate (CR + PR + stable disease [SD]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II)

TERTIARY OBJECTIVES:

I. To evaluate the ability of AZD1775 to inhibit Wee1 and increase deoxyribonucleic acid (DNA) damage and tumor cell death when combined with nab-paclitaxel/gemcitabine compared to nab-paclitaxel/gemcitabine/placebo. (Phase II) II. To evaluate if biomarker changes in tumor tissue associated with Wee1 inhibition may also be present in hair follicles. (Phase II) III. To evaluate the change in tumor fludeoxyglucose (FDG) uptake (maximum standardized uptake value [SUVmax]) between baseline FDG-positron emission tomography (PET) and week 4 FDG-PET as a predictor of response using Response Evaluation Criteria in Solid Tumors (RECIST) as the reference standard for response. (Phase II) IV. To evaluate the change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET as a predictor of progression-free survival. (Phase II) V. To compare the change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET between the patients from treatment arms C and D. (Phase II) VI. To evaluate if an early increase in tumor fluorothymidine (FLT) uptake (FLT-flare) is observed within 24 hours after initiation of treatment with nab-paclitaxel/gemcitabine/placebo. (Phase II) VII. To evaluate if an early (within 24 hours [h]) increase in tumor FLT uptake (FLT-flare) is abrogated after initiation of treatment with nab-paclitaxel/gemcitabine/AZD1775. (Phase II) VIII. To compare the change in tumor FLT uptake (SUVmax) from baseline to 24 hours after initiation of treatment between the patients from treatment arms C and D. (Phase II)

OUTLINE: This is a phase I, dose escalation study of WEE1 inhibitor MK-1775 followed by a randomized phase II study. Patients in phase I are assigned to arm A or B and patients in phase II are randomized to arm C or D.

ARM A (PHASE I, DOSE LEVEL 1): Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor MK-1775 orally (PO) daily on days 1, 2, 8, 9, 15, and 16.

ARM B (PHASE I, DOSE LEVEL 2): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor MK-1775 as in Arm A.

ARM C (PHASE II, PLACEBO): Patients receive paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride as in Arm A. Patients also receive placebo PO daily on days 1, 2, 8, 9, 15, and 16.

ARM D (PHASE II, WEE1 INHIBITOR MK-1775): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor MK-1775 as in Arm A.

In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Metastatic Pancreatic Adenocarcinoma
• Stage III Pancreatic Cancer AJCC v6 and v7
• Stage IV Pancreatic Cancer AJCC v6 and v7
• Unresectable Pancreatic Carcinoma

Intervention

• Drug: Adavosertib
  Given PO
  Other Names:

  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775
• Drug: Gemcitabine Hydrochloride
  Given IV
  Other Names:

  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Nab-paclitaxel
  Given IV
  Other Names:

  • ABI 007
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • Paclitaxel Albumin
  • paclitaxel albumin-stabilized nanoparticle formulation
  • Protein-bound Paclitaxel
• Other: Pharmacological Study
  Correlative studies
• Other: Placebo Administration
  Given PO

Study Arms

• Experimental: Arm A (phase I, dose level 1)
  Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor MK-1775 PO daily on days 1, 2, 8, 9, 15, and 16.
  Interventions:

  • Drug: Adavosertib
  • Drug: Gemcitabine Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Drug: Nab-paclitaxel
  • Other: Pharmacological Study
• Experimental: Arm B (phase I, dose level 2)
  Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor MK-1775 as in Arm A.
  Interventions:

  • Drug: Adavosertib
  • Drug: Gemcitabine Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Drug: Nab-paclitaxel
  • Other: Pharmacological Study
• Active Comparator: Arm C (phase II, placebo)
  Patients receive paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride as in Arm A. Patients also receive placebo PO daily on days 1, 2, 8, 9, 15, and 16.
  Interventions:

  • Drug: Gemcitabine Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Drug: Nab-paclitaxel
  • Other: Pharmacological Study
  • Other: Placebo Administration
• Experimental: Arm D (phase II, WEE1 inhibitor MK-1775)
  Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor MK-1775 (recommended phase II dose) as in Arm A.
  Interventions:

  • Drug: Adavosertib
  • Drug: Gemcitabine Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Drug: Nab-paclitaxel
  • Other: Pharmacological Study

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 16, 2014): 133
• Original Estimated Enrollment: Same as current
• Study Completion Date: Not Provided
• Estimated Primary Completion Date: May 21, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• PHASE I STUDY -- ARM A (DOSE LEVEL 1) AND ARM B (DOSE LEVEL 2)
• Patients must have histologically or cytologically confirmed metastatic or unresectable locally advanced adenocarcinoma of the pancreas with no prior systemic therapy for metastatic or locally advanced disease
• Previous neo-adjuvant or adjuvant treatment is allowed provided that it was given >= 6 months prior to registration
• Patients must NOT be receiving any other investigational agents concurrently and must not have received any other investigational agents =< 4 weeks prior to registration
• Patients must not have a pre-existing > grade 1 motor or sensory neuropathy
• Patients must NOT have history of allergic reactions attributed to compounds of similar chemical or biologic composition to nab-paclitaxel, gemcitabine or AZD1775
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patients must have a life expectancy of >= 12 weeks
• Patients may have had prior radiotherapy for metastatic disease as long as it was > 4 weeks prior to registration and the patient has recovered from adverse events associated with the radiotherapy
• Patients must NOT be taking current medications or substances that are inhibitors or inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4)
• Patients must NOT have uncontrolled serious medical illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements
• Patients with known human immunodeficiency virus (HIV) are not eligible if cluster of differentiation (CD)4 count is =< 200 cell/mm^3 or if receiving antiretroviral therapy
• Patients must be able to swallow capsules whole

• Patients must NOT have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:

  • Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)
  • Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years
• Patients must be able to tolerate computed tomography (CT), magnetic resonance imaging (MRI) or PET imaging including contrast agents

• Women must not be pregnant or breast-feeding

  • Females of childbearing potential must have a blood test or urine study within 5 days prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal and barrier method of birth control; two barrier methods of birth control; abstinence) for the duration of study treatment and for 3 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; should a man impregnate or suspect that he has impregnated a woman while participating in this study, he should inform his treating physician immediately
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Hemoglobin >= 9 g/dL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X institutional upper limit of normal (ULN) or =< 5 X ULN if the patient has liver metastases
• Creatinine =< 1.5 mg/dL or creatinine clearance (Cockcroft-Gault) >= 60 mL/min for patients with creatinine levels above institutional upper limit of normal (ULN)
• RANDOMIZED PHASE II STUDY -- ARMS C AND D
• PHASE II: Patients must have histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas with no prior systemic therapy for metastatic disease
• PHASE II: Patients must NOT have locally advanced disease
• PHASE II: Patients must have measurable disease outside of the primary tumor (pancreas) by RECIST 1.1 criteria; baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to randomization
• PHASE II: Previous neo-adjuvant or adjuvant treatment is allowed provided that there was no evidence of recurrent disease for at least 6 months after completion of neo-adjuvant/adjuvant treatment
• PHASE II: Patients may have had prior radiotherapy for metastatic disease as long as it was > 4 weeks prior to randomization and the patient has recovered from adverse events associated with the radiotherapy
• PHASE II: Patients must NOT be taking current medications or substances that are inhibitors or inducers of CYP3A4
• PHASE II: Patients must NOT have received prior Wee1 inhibitors or AZD1775
• PHASE II: Patients must NOT have received gemcitabine or nab-paclitaxel in a metastatic setting
• PHASE II: Patients must NOT be receiving any other investigational agents concurrently and must not have received any other investigational agents =< 4 weeks prior to randomization
• PHASE II: Patients must not have a pre-existing > grade 1 motor or sensory neuropathy
• PHASE II: Patients must NOT have history of allergic reactions attributed to compounds of similar chemical or biologic composition to nab-paclitaxel, gemcitabine or AZD1775
• PHASE II: Patients must have ECOG performance status of 0 or 1
• PHASE II: Patients must have a life expectancy of >= 12 weeks
• PHASE II: Patients must NOT have uncontrolled serious medical illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements
• PHASE II: Patients must be able to swallow capsules whole
• PHASE II: Patients with biliary stents are allowed

• PHASE II: Patients must NOT have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:

  • Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ) • Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years
• PHASE II: Patients must be able to tolerate CT, MRI or PET imaging including contrast agents

• PHASE II: Women must not be pregnant or breast-feeding

  • Females of childbearing potential must have a blood test or urine study within 5 days prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• PHASE II: Women of child-bearing potential and men must agree to use adequate contraception (hormonal and barrier method of birth control; two barrier methods of birth control; abstinence) for the duration of study treatment and for 3 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; should a man impregnate or suspect that he has impregnated a woman while participating in this study, he should inform his treating physician immediately
• PHASE II: Leukocytes >= 3,000/mcL
• PHASE II: Absolute neutrophil count >= 1,500/mcL
• PHASE II: Hemoglobin >= 9 g/dL
• PHASE II: Platelets >= 100,000/mcL
• PHASE II: Total bilirubin =< 1.5 institutional upper limit of normal (ULN)
• PHASE II: AST (SGOT)/ALT (SGPT) =< 3 X institutional upper limit of normal (ULN) or =< 5 X ULN if the patient has liver metastases
• PHASE II: Creatinine =< 1.5 mg/dL or creatinine clearance (Cockcroft-Gault) >= 60 mL/min for patients with creatinine levels above institutional upper limit of normal (ULN)
• PHASE II: For participation in the imaging research studies, patients must meet the additional following criteria:
• PHASE II: The patient is participating in the trial at an institutional which has agreed to perform the imaging research studies, completed the American College of Radiation Imaging Network (ACRIN) defined scanner qualification procedures and received ACRIN approval
• PHASE II: The patient has consented in writing to participate in one of the imaging research studies

• PHASE II: The patient meets the criteria required for the imaging study in which the site is participating:

  • NOTE: Eligibility for participating in either imaging sub-study will depend on the availability of the imaging sub-study at a particular institution

  • For participation in the FDG-PET sub-study:

    • Patients must NOT have poorly controlled diabetes (defined as fasting glucose level >= 200 mg/dL) despite efforts to improve glucose control by fasting duration and adjustment of medications
    • Patient must NOT weigh more than the maximum weight limit for the PET table
    • Patients must have an evaluable lesion of > 20 mm in size on standard practice imaging study as assessed by site (either primary pancreas mass or metastasis)

  • For participation in the FLT-PET sub-study:

    • Patients must be able to lie still for a 1.5 hour PET scan.
    • Patient must NOT have a history of allergic reaction attributable to compounds of similar chemical or biologic composition to 18F-fluorothymidine
    • Patient must NOT weigh more than the maximum weight limit for the PET table
    • Patients must have an evaluable lesion in the pancreas > 20 mm in size on standard practice imaging study as assessed by site (lesion must be likely primary adenocarcinoma of the pancreas that is not primarily fibrotic or mucinous in nature)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02194829
• Other Study ID Numbers: NCI-2014-01425; NCI-2014-01425 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); E1213; EA2131 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA2131 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract ); U10CA021115 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jennifer R Eads; ECOG-ACRIN Cancer Research Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: December 2020